Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and is one of the most prevalent malignancies in Asia and locally in Hong Kong. Currently, the front-line treatment regimen for HCC includes hepatic resection and liver transplantation. However, these two potentially curative treatment options are limited by several factors, for example, (i) advanced stage at which the disease is usually diagnosed, (ii) underlying cirrhosis and poor hepatic reserve commonly associated with these patients, and (iii) shortage of available liver grafts.
It has been estimated that only 25% of the patients with HCC are eligible for potential curative treatments at the time of presentation. Several local ablation treatment protocols, such as percutaneous ethanol injection (PEI) or radiofrequency ablation (RFA), are also commonly practiced in cases of limited disease; but these methods are mainly for palliation and are applicable only to patients who meet stringent criteria with tumors localized to liver.
Chemotherapy either via transarterial chemoembolization (TACE) or systemic treatment is also available and is also administered as a pre-/post-surgical adjuvant therapy, yet the overall response rate to this treatment is low due to the highly chemotherapy resistant nature of HCC. Thus, there is an urgent need to elucidate the key genes in relation to recurrence and chemo-resistance in HCC, to develop better diagnostic and prognostic biomarkers for detection of HCC at an earlier stage, and to develop novel therapeutic approaches to more effectively treat the disease.
As molecular indicators of biological status, biomarkers detectable in blood can be useful for the clinical management of various disease states. Threshold concentrations can be utilized to identify the presence of various diseases. Common cancer biomarkers include prostate specific antigen (PSA) for prostate cancer and cancer antigen 125 (CA125) for ovarian cancer. Currently, serum α-fetoprotein (AFP) has been widely used for HCC diagnosis (MacDonald and Kelly, 1978). However, the serum AFP cut-off for detecting HCC in patients with co-existing liver diseases has not reached consensus with values ranging from 10 to 500 ng/ml (Taketa 1990, Johnson 2001, Gebo et al., 2002). The serum AFP test when used with the conventional higher cut-off point of 500 ng/ml revealed a sensitivity of about 50% and a specificity of more than 90% in detecting the presence of HCC in patients with co-existing liver disease (Johnson 2001). When used with lower cut-off values between 10 and 19 ng/ml, the sensitivity of the serum AFP test was 45% to 100% and with a specificity of 70% to 95% (Gebo et al., 2002).
Other common biomarkers for HCC include glypican-3 and des-gamma-carboxy prothrombin (DCP), but their uses are also limited in their sensitivity and specificity.
Therefore, the identification of a novel biomarker with better sensitivity and specificity is urgently required for a better diagnosis and prognosis of HCC.
With the advent of hybridoma technology for the production of humanized and murine-human chimeric monoclonal antibody, targeted cancer therapy can be achieved by the use of monoclonal antibodies (Adams and Weiner 2005). Monoclonal antibody therapy is proven to be effective in cancer treatment, for example, the use of anti-CD20 monoclonal antibody (Rituximab) for B-cell lymphoma (von Schilling 2003), anti-Her2 neutralizing monoclonal antibody (Herceptin) for metastatic breast cancer (Shak 1999, Willems et al., 2005) and anti-EGFR and anti-VEGF for metastatic colorectal cancer (Vanhoefer et al., 2004, Fernando and Hurwitz 2004). In fact, many monoclonal antibodies are currently undergoing clinical trials; thus further suggesting the usefulness of monoclonal antibodies for therapeutic purposes. Current molecular targets for the treatment of HCC are restricted to several cell signaling pathways, like EGFR, IGF-R1, PI3K/AKT/mTOR, RAS/RAF/MAPK, VEGF, etc., and although with some success, molecular targeted therapies (including monoclonal antibodies and small molecule inhibitors) for other pathways would be beneficial in HCC treatment.
ANXA3 belongs to the annexin family of Ca2+-dependent phospholipid-binding proteins (Wu et al., 2013). Up-regulation of ANXA3 expression was recently detected in various tumor types including prostate, ovarian, lung, and breast cancers (Wozny et al., 2007, Kollermann et al., 2008, Schostak et al., 2009, Thoenes et al., 2010, Yan et al., 2007, Yan et al., 2010, Liu et al., 2009; Zeng et al., 2013). Serum ANXA3 levels were also found to be significantly up-regulated in ovarian cancer patients compared with healthy individuals (Yin et al., 2012). Furthermore, overexpression of ANXA3 was found to contribute to platinum resistance in ovarian cancer (Yan et al., 2007, Yan et al., 2010). Two recent studies have also found ANXA3 to be preferentially expressed in the CD133+ liver cancer stem cell subset (Tsai et al., Proteome Sci 2012) and that ANXA3 is associated with multi-drug resistance (MDR) in 5-fluorouracil-resistant HCC cells BEL7402 (Tong et al., J Cell Biochem 2012). Yet, to date, no studies have addressed the clinical significance of endogenous and secretory ANXA3 in HCC, the role of ANXA3 in driving hepato-carcinogenesis, or the use of anti-ANAX3 antibody as a therapeutic regimen against HCC.